This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have constructed new strains of simian-human immunodeficiency virus (SHIV), viruses that are part monkey AIDS virus (termed SIV), part human AIDS virus (termed HIV-1). One of these, SHIV-Bo159N4, encodes the envelope gene of a primary HIV-1 that was adapted in human brain-derived cells. SHIV-Bo159N4 replicated well in blood cells of all monkeys tested and enters cells via CCR5 and forms giant cells containing many nuclei. We inoculated rhesus monkeys (RM) intravenously and mucosally with this new virus. To increase viremia, CD8+ cells and B cells were depleted shortly after inoculation;high viral RNA levels were seen in plasma and cerebrospinal fluid (CSF). We also inoculated pigtailed monkeys under depletion of CD8+ cells;again, high viral loads were observed in plasma and CSF. Animals with the highest CSF viral RNA loads were euthanized, microglia were isolated and transferred to new recipients. Brain sections are being tested for evidence of productive viral infection and brain disease. We are currently following chronically infected RM and pigtailed monkeys for disease. We have also constructed SHIV-KNH1144, which encodes the envelope gene of an African clade A HIV-1 strain. SHIV-KNH1144 was adapted to RM, a large virus stock was generated and is undergoing analysis. Next, we showed that passive immunization with a novel human monoclonal antibody (mAb) isolated from an HIV-infected person completely protected infant RM against mucosal challenge with a neutralization-sensitive SHIV containing an HIV clade C envelope. This is the first demonstration that a neutralizing mAb can protect across different clades.